This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rib-X Pharmaceuticals, Inc. is a small molecule drug discovery and development company whose goal is to address the medical difficulties presented by increasing bacterial resistance against current antibacterial agents by developing novel chemical classes of anti-infective molecules that target the ribosome. In order to shorten thedrug discovery process, we employ a structure-based design strategy that utilizes high resolution crystal structures of the 50S ribosome from the archaeal Haloarcula marismortui, complexed with small molecule inhibitors. Importantly, our research has already led to the identification of multiple clinical candidates with novel antibiotic properties for treating resistant infections. To augment our continuing drug discovery efforts, we have recently crystallized and determined the high resolution structure of the 50S ribosomal subunit from a Gram-positive bacterium. This allows us to target 50S regions not conserved between archeal and eubacterial kingdoms. Given the very large unit cell dimensions of our archeal and eubacterial 50S crystals, we are constrained to use not only a high intensity synchrotron source for x-rays, but also the best beamlines in terms of brightness, beam collimation and detector size, such as those found at NSLS.